The American Journal on Addictions, 23: 308–312, 2014 Copyright © American Academy of Addiction Psychiatry ISSN: 1055-0496 print / 1521-0391 online DOI: 10.1111/j.1521-0391.2014.12126.x
Ziprasidone Versus Clozapine in the Treatment of Dually Diagnosed (DD) Patients With Schizophrenia and Cannabis Use Disorders: A Randomized Study Thomas Schnell, PhD, Dagmar Koethe, MD, Anna Krasnianski, MD, Stefanie Gairing, MD, Knut Schnell, MD, Jörg Daumann, PhD, Euphrosyne Gouzoulis‐Mayfrank, MD Department of Psychiatry and Psychotherapy, University Hospital of Cologne, Cologne, Germany
Background and Objectives: Clozapine is considered to be particularly effective in the treatment of dually diagnosed (DD) patients with psychosis and substance use disorders. However, its use is restricted by potentially severe side effects. The aim of the present pilot study was to compare the effects of clozapine with the newer second generation antipsychotic (SGA) ziprasidone in DD‐patients. Methods: Thirty (n ¼ 30) patients with schizophrenia and cannabis abuse/dependence were randomized to ziprasidone or clozapine and were followed up for up to 12 months. Results: Cannabis use was reduced in both groups during follow‐up. Clozapine treatment was associated with less positive symptoms of schizophrenia, more side effects and poorer compliance with treatment. Conclusions: Results from this small pilot RCT suggest beneficial effects of both clozapine and ziprasidone in the treatment of cannabis use disorders in psychotic patients. Larger‐scale RCTs are needed in order to assess advantages and disadvantages of the different SGAs in dually diagnosed populations. (Am J Addict 2014;23:308–312)
INTRODUCTION Cannabis use is associated with negative impact on long‐term rehabilitation results in patients with schizophrenia.1 Concerning pharmacologic treatment strategies for patients with
Received April 15, 2013; revised September 29, 2013; accepted October 6, 2013. The present address of Thomas Schnell PhD is Medical School Hamburg (MSH), Am Kaiserkai 1, 20457 Hamburg, Germany. The present address of Dagmar Koethe MD and Knut Schnell MD are Department of Psychiatry and Psychotherapy, University Hospital of Heidelberg, Voßstr. 2, 69115 Heidelberg, Germany. The present address of Euphrosyne Gouzoulis-Mayfrank MD is LVR Clinics Cologne, Wilhelm‐Griesinger Str. 23, 51109 Cologne, Germany. Grant sponsor: Pfizer Pharma. Address correspondence to Dr. Gouzoulis‐Mayfrank, Department of Psychiatry and Psychotherapy, University Hospital of Cologne, Kerpener Str. 62, 50924 Cologne, Germany. E‐mail: [email protected] 308
schizophrenia and comorbid substance use disorders (Dual Diagnosis ¼ DD patients), first generation antipsychotic medications (FGA) may have a negative impact on drug use behavior for two reasons. First, some side effects of FGAs resemble negative symptoms of psychosis, and they may facilitate the urge for self‐medication with drugs or alcohol. Second, as most FDAs are potent selective blockers of dopamine D2 receptors, their direct pharmacologic mechanisms may compromise mesolimbic reward systems, and this may promote addictive behaviors.2,3 Second generation antipsychotics (SGA) are considered helpful in terms of reducing drug use in DD patients, and this may relate to their broader pharmacologic mechanisms affecting dopaminergic and serotonergic systems and their positive impact on negative symptoms.4,5 However, evidence from controlled studies is limited. Clozapine is considered to be particularly effective in the treatment of DD patients, however the evidence mainly derives from uncontrolled studies and case series supporting beneficial effects on psychopathology and craving or drug use.6–10 Only one small randomized study reported diminished use of cannabis in DD patients who were switched from other antipsychotics to clozapine; however, it is not clear whether the previous medication included SGAs or FGAs or both.11 Nevertheless, given the potentially life threatening side effect of agranulocytosis, clozapine is not a first‐line antipsychotic. Many patients will not comply with the required laboratory blood tests or they will not tolerate other common side effects of clozapine such as sedation and weight gain. The main objective of our randomized pilot trial was to study cannabis use behavior in DD patients treated with clozapine compared to another SGA. We chose to study ziprasidone because of its relatively favorable side effect profile which does not include sedation or weight gain, and because of its pharmacological properties. Both clozapine and ziprasidone exhibit a relatively broad receptor profile with only moderate affinities to dopamine and higher affinities to serotonin‐receptors, and this is considered to be advantageous in respect to addiction mechanisms.5 In addition, clozapine
enhances glutamatergic NMDA mechanisms, and this may help to alleviate craving for drugs of abuse.12,13 Finally, ziprasidone inhibits serotonin and noradrenalin reuptake, and this may result in antidepressive effects, which, in turn, may help to reduce relief‐craving in DD patients.14 Hence, both clozapine and ziprasidone may be suitable medications for the treatment of DD patients.
METHODS This pilot study was performed in accordance with the Helsinki Declaration (1964) and was approved by the local ethics committee of the University of Cologne, Germany. After full verbal and written information about the study, patients gave written informed consent for their participation with the explicit notion that they were free to withdraw their consent at any time without having to disclose the reasons and without any consequences for their further treatment. The study was registered in EudraCT (European Union Drug Regulating Authorities Clinical Trials, EudraCT‐Number: 2005‐003156‐35). Participants We planned to randomize 50 dually diagnosed in‐patients with schizophrenia, schizophreniform or schizoaffective disorder according to DSM‐IV as well as cannabis abuse or dependence according to DSM‐IV to either ziprasidone or clozapine treatment. Exclusion criteria were further Axis I psychiatric disorders or relevant neurologic disorders affecting brain function and acute positive symptoms interfering with the capability to give informed consent. Study Procedures At baseline (t0), we reviewed the medical records of all patients and performed a detailed interview on demographics, a Structured Clinical Interview (SCID I for DSM‐IV)15 and an additional detailed interview on patterns of cannabis use including age at onset of use, time since last use, average frequency of use (joints per month) and maximum frequency of use (joints per month), duration of regular cannabis use (months), as well as the age at onset of the psychotic disorder. Psychiatric symptoms and level of functioning were assessed by one single rater (T.S.) by means of the PANSS,16 Montgomery Asberg Depression Scale17 and the Global Assessment of Functioning Scale (GAF) according to DSM‐ IV.15 The UKU Side Effect Rating Scale18 was used to assess side effects of medication and the Drug Attitude Inventory19 to evaluate compliance with the medication (indicator of medication adherence). The motivation to stop or reduce cannabis use was assessed by means of the standardized questionnaire SOCRATES.20 After completion of the baseline assessments, patients were randomized to treatment with ziprasidone or clozapine. Treatment allocation was concealed in 50 opaque, security‐ sealed envelopes, which were held in a packet in a locked Schnell et al.
cabinet. Envelopes contained a sheet of paper typed with clozapine or ziprasidone (25 envelopes each). Randomization was conducted by a person independent to the study by means of randomly drawing and opening an envelope from the packet. The result of randomization was given to the study administrator, who informed the attending psychiatrist of the patient’s treatment allocation. After randomization, drug dosage and concomitant medications were flexible and adjustable depending on clinical requirements. There were no limitations in doses, concomitant medications and combinations. Decisions for drop‐out from study medications were taken by the attending psychiatrist together with the patient on the basis of clinical evaluations of effectiveness and/ or side effects. After discharge from hospital, all patients were offered integrated treatment for both the psychotic and drug use disorder in the out‐patient unit of the Department. The treatment included pharmacotherapy, clinical management with supportive and motivational elements, psychoeducation, cognitive behavioral group therapy and support for social and occupational rehabilitation. Patients underwent follow‐up assessments by the same rater (T.S.) at fixed time points 3, 6, and 12 months after inclusion in the study (t1, t2, t3), irrespective of the actual medication and setting in which they were treated (out‐patient unit of the Department or again in‐ patient setting after readmission). At follow‐up assessments, we reviewed the medical records and performed detailed interviews with the patients, a family member or significant other and the attending psychiatrist. We verified compliance with the antipsychotic drug regimen by means of assessments of drug plasma levels (Institute of Neurochemistry, University Hospital of Mainz, Department of Psychiatry and Psychotherapy). We assessed cannabis use during the months since the last visit (primary outcome variable: average frequency of use in joints per month). Finally, we complemented the interview results by toxicological screens in urine samples (enzyme‐ multiplied immunoassay, von Minden GmbH) and toxicological hair analysis (Institute of Legal Medicine of the University of Cologne). In addition, we evaluated the overall clinical course, assessed exacerbations of the psychotic disorder and rehospitalizations, compliance with the treatment (operationalized as percentage of completed vs. scheduled therapy sessions) and unscheduled presentations on an emergency basis. Finally, we assessed psychopathology, side effects and compliance with medication and motivation to reduce drug use by means of the same standardized instruments as in the baseline examination. Statistical analyses We performed both Intention to Treat (ITT) and Treated per Protocol analyses (TPP). Regarding the ITT condition, we applied the last observation carried forward (LOCF) method as a very conservative means of analysis with the data of all patients who reached the first follow‐up examination (t1). Demographic variables and baseline clinical characteristics were compared between groups by means of chi‐square and May–June 2014
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unpaired t tests. Regarding the analyses of follow‐up data, we compared the two groups by means of multivariate analyses of variance (MANCOVA) with repeated measurements including two covariates1 length of time of initiating inpatient treatment and2 follow‐up treatment setting (inpatient, day hospital, and outpatient). Levels of significance were corrected according to Bonferroni. All procedures were performed using SPSS version 15 (SPSS, Inc., Chicago, IL).
RESULTS Thirty patients were included in the study, 16 patients were randomized to receive ziprasidone treatment and 14 received clozapine. The study had to be closed after the 30 patients because of circumstances unrelated to the study (move of the principal investigator to another institution). The sample was predominantly male (86.7%) with a mean age of 29 years (SD 8.1). On average, the first psychotic episode had been 43.9 months prior to inclusion in the study (SD 36.4), patients had
experienced on average 5 previous psychotic episodes (SD 9.2). Regarding cannabis use disorders, 27 patients were diagnosed with dependence, and 3 patients with cannabis abuse. There were no significant differences between the two groups with respect to demographic and baseline clinical characteristics (Table 1). The average daily dose of clozapine was 225 mg (range: 50–425 mg), and the average dose of ziprasidone was 200 mg (range: 80–400 mg). Antipsychotic drug plasma levels were compatible with the prescribed doses. Twelve out of the 30 patients finished the study regularly after the treatment period of one year (7 patients in the ziprasidone group, 5 patients in the clozapine group). Eleven patients dropped out before t1, 5 patients before t2 and 2 patients before t3. Reasons for drop outs in the clozapine group were: sedation (n ¼ 7), extreme hypersalivation (n ¼ 1) and fever (n ¼ 1). Reasons for drop outs in the ziprasidone group were: agitation (n ¼ 2) and insufficient antipsychotic efficacy (n ¼ 7). There were significant differences concerning co‐medications between groups (chi‐square ¼ 11.72; p ¼ .039). Patients
TABLE 1. Comparison of demographic and baseline‐data (t0) between groups
Descriptive statistics
Gender (male/female) Mean age in years (mean, SD) Level of graduation Employment† Partnership (single/with partner) Housing‡ Time since diagnosed with schizophrenia (months, mean and SD) Mean age in years at onset of cannabis use (mean, SD) Number of psychotic episodes (mean, SD) Time between onset of cannabis use and diagnosed with schizophrenia (months, mean, and SD) Time since last cannabis use (days, mean, and SD) Average frequency of cannabis use (joints per month) Maximum frequency of cannabis use (joints per month) Duration of regular cannabis use (months, mean and SD) PANSS positive symptoms (mean, SD) PANSS negative symptoms (mean, SD) PANSS general psychopathology (mean, SD) MADRS (mean, SD) GAF score (mean, SD) DAI (mean, SD) SOCRATES taking steps (mean, SD) SOCRATES recognition (mean, SD) SOCRATES ambivalence (mean, SD)
Statistics
Ziprasidone (n ¼ 16)
Clozapine (n ¼ 14)
df
Value
p
14/2 27.5 (5.0) 1/5/4/4/2 13/0/2/0/1 16/0 10/5/0/0/1 39.69 (33.79) 16.13 (2.39) 3.4 (3.5) 82.38 (40.76)
12/2 30.71 (10.5) 2/4/7/0/1 12/1/0/1/0 14/0 9/2/1/1/1 48.71 (40.08) 17.43 (4.52) 6.9 (12.8) 80.79 (70.53)
1 28 4 4 1 4 28 28 28 28
021§ 1.089¶ 1.211|| 4.929§ x 3.219§ .669¶ 1.006¶ 1.108¶ .077¶
.886 .286 .236 .295 x .522 .509 .323 .277 .939
46.88 (61.68) 115.5 (147.94) 340.38 (303.37) 97.50 (40.55) 13.75 (2.69) 13.50 (6.45) 33.63 (7.1) 13.56 (4.86) 47.25 (11.78) .25 (4.84) 6.93 (4.29) 2.18 (3.14) 1.56 (2.03)
23.57 (23.52) 114.14 (228.48) 302.14 (216.48) 114.64 (91.65) 15.57 (5.47) 17.93 (10.2) 38.21 (6.46) 14.79 (6.67) 43.36 (8.75) .43 (3.85) 7.35 (5.42) 1.5 (2.21) .85 (1.35)
28 28 28 28 28 28 28 28 28 28 28 28 28
1.329¶ .020¶ .392¶ .678¶ 1.180¶ 1.440¶ 1.842¶ .579¶ 1.015¶ .111¶ .236¶ .683¶ 1.102¶
.195 .985 .698 .504 .248 .161 .076 .567 .319 .913 .815 .500 .280
None/elementary school degree after form 9/intermediate school degree after form 10/A‐level after form 13/university degree;; †Jobless/full job/part time job/ pension/other;; ‡Alone/with family/assisted living/homeless/other;; §Chi‐square;; ¶T‐Value;; ||Z‐Value (Mann–Whitney U‐test); df, degrees of freedom; SD, standard deviation; p, level of significance; PANSS, positive and negative syndrome scale; MADRS, Montgomery‐Asberg Depression Rating Scale; GAF, global assessment of functioning scale; DAI, drug attitude inventory; SOCRATES, stages of change readiness and treatment eagerness scale.
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treated with ziprasidone were more likely to get additional antipsychotics, whereas patients treated with clozapine were more likely to get antidepressant co‐medications. There was no significant difference in time‐to‐dropout between the two groups (chi‐square ¼ 2.5; p ¼ .475). Regarding the primary outcome variable (average frequency of cannabis use) LOCF analysis as well as the TPP analysis with the patients who reached the last observation point after 12 months, yielded comparable findings. The data are presented in Figure 1. No patient had to be excluded from analyses due of incompatibilities between the different sources of data information (medical records, interviews with patients, significant others and the attending psychiatrist, toxicological screens in urine, and hair samples). The two covariates (length of time of initiating inpatient treatment and follow‐up treatment setting (inpatient, day hospital and outpatient)) were below significance at all follow‐up examinations (p > .08). Hereafter, we present the data of the TPP analysis. The complete statistical analyses can be obtained upon request from the first author. Both groups reduced the frequency of cannabis consumption during follow‐up (main effect of time: F ¼ 7.15; p ¼ .023). The reduction of cannabis use was already seen at the first follow‐up examination (t1) and was stable over the period of 12 months with no differences between the two
A
ITT analysis (LOCF)
400 350 300 250 200
Ziprasidone (n=11)
150
Clozapine (n=8)
100 50 0 t0
t1
B
t2
t3
TPP analysis
450 400 350 300 250
Ziprasidone (n=7)
200
Clozapine (n=5)
150 100 50 0 t0
t1
t2
t3
FIGURE 1. Frequency of cannabis use (joints per month, means and SD) during baseline (t0) and follow‐up examinations (t1: 3 months, t2: 6 months, t3: 12 months after baseline), according to both ITT (1a) and TPP analysis (1b). ITT, intention to treat; LOCF, last observation carried forward; TPP, treatment per protocol.
Schnell et al.
groups (main effect of group: F ¼ 2.75; p ¼ .128) and no interaction time treatment (F ¼ 2.14; p ¼ .174). The PANSS positive scale score decreased over time for both groups (main effect of time: F ¼ 5.37; p ¼ .004). The group effect was below significance (F ¼ 2.811; p ¼ .056). However, the interaction effect (time treatment) was significant and pointed to a stronger decline of positive symptoms in the clozapine group (F ¼ 3.11; p ¼ .05). In line with that, there was a significant between‐group effect concerning treatments on an emergency basis with more consultations in the ziprasidone group (F ¼ 7.29; p ¼ .022). Further significant time treatment interactions were identified regarding compliance with treatment. Patients treated with ziprasidone evaluated their medication more positively (score of the drug attitude inventory) and they attended more regularly their group psychotherapy sessions (F ¼ 5.21; p ¼ .005, and F ¼ 4.51; p ¼ .024, respectively). Finally, there was a significant between‐group effect on side effects unfavoring the clozapine group (F ¼ 8.2; p ¼ .017). A detailed analysis of the UKU Rating Scale data on a single item level revealed that this was primarily due to hypersalivation.
DISCUSSION The present pilot study aimed to compare the effects of clozapine and ziprasidone on cannabis use in dually diagnosed (DD) patients with psychosis and cannabis use disorder. Thirty DD patients were randomized to ziprasidone or clozapine and were followed up for up to 12 months. Both antipsychotics were followed by improvement of psychotic symptoms and reductions of cannabis use. Clozapine treatment was associated with a stronger reduction of positive symptoms, but more side effects. Patients treated with ziprasidone evaluated the medication more positively and they showed an overall higher adherence with the psychosocial treatment compared to the clozapine group (more frequent attendance of group psychotherapy sessions). Our findings suggest that besides clozapine, ziprasidone (and probably also other SGAs) may also be suitable medications for the treatment of dually diagnosed patients. Hence, the clinical decision for an antipsychotic medication should be based on the clinical symptom profile of the individual patient such as withdrawal and apathy or agitation, and on the side effect profile of the antipsychotic drug favoring activation or sedation. Interestingly, some of the patients in the present trial felt that the sedating effects of clozapine helped to diminish craving for cannabis, while other patients suffered from sedation. Some patients treated with ziprasidone appreciated the activating effects of this medication, whereas two patients reported that some (over)excitement after ziprasidone was associated with stronger craving. Several important limitations of this study have to be acknowledged: First, the sample size was small and drop‐out rates were high, and this can easily skew the results. Furthermore, very few patients treated with clozapine finished May–June 2014
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the study, and clozapine is known to require several months to reach its full efficacy. Second, both patients and raters were not blind to the treatment condition. Third, the attending doctors were allowed to adjust the dose of the study medications and give co‐medications according to clinical requirements, and this renders conclusions on the effects of the study medications difficult. Finally, less specific aspects of treatment and care, such as the participation in the clinical trial, the increased attention and general support and the psychotherapeutic program may have contributed to the reduction of substance use in both groups. In conclusion, the present pilot study has important methodological limitations. Nevertheless, it does suggest that both clozapine and newer SGAs may be suitable medications for the treatment of DD patients. Larger‐scale RCTs are needed in order to assess advantages and disadvantages of different SGAs in this population. In the meanwhile, clinicians should come to individual decisions based on the symptom profile and preferences of the individual patients as well as the effects and side effect profile of the different SGAs. The present study was supported by a grant from Pfizer Pharma (Karlsruhe, Germany) to the last author (investigator initiated trial). Apart from financial support, Pfizer had no influence on any aspect of the study such as design, data collection, statistical analyses, interpretation of data and drafting the manuscript. The authors thank Prof. Dr. C. Hiemke (Institute of Neurochemistry, University Hospital of Mainz) for the assessments of drug plasma levels, and Prof. Dr. H. Käferstein (Institute of Legal Medicine, University Hospital of Cologne) for the toxicological hair analyses. Declaration of Interest This investigator initiated trial (IIT) was supported by Pfizer Pharma. Authors report no other conflicts of interest.
REFERENCES 1. Moore THM, Zammit S, Lingford‐Hughes A, et al. Cannabis use and risk of psychotic or affective mental outcomes: A systematic review. Lancet. 2007;370:319–328. 2. Green AI. Schizophrenia and comorbid substance use disorder: Effects of antipsychotics. J Clin Psychiatry. 2006;66(Suppl. 6):21–26.
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3. Sayers SL, Campbell EC, Kondrich J, et al. Cocaine abuse in schizophrenic patients treated with olanzapine versus haloperidol. J Nerv Ment Dis. 2005;193:379–386. 4. Baker AL, Hides L, Lubman DI. Treatment of cannabis use among people with psychotic or depressive disorders: A systematic review. J Clin Psychiatry. 2010;71:247–254. 5. Wobrock T, Soyka M. Pharmacotherapy of schizophrenia with comorbid substance use disorder—Reviewing the evidence and clinical recommendations. Prog Neuropsychopharm Biol Psychiatry. 2008;32: 1375–1385. 6. Lubman DI, King JA, Castle DJ. Treating comorbid substance use disorders in schizophrenia. Int Rev Psychiatry. 2010;22:191–201. 7. Kelly TM, Daley DC, Douaihy AB. Treatment of substance abusing patients with comorbid psychiatric disorders. Addict Behav. 2012;37: 1–24. 8. Murthy P, Chand P. Treatment of dual diagnosis disorders. Curr Opin Psychiatry. 2012;25:194–200. 9. Zimmet SV, Strous RD, Burgess ES, et al. Effects of clozapine on substance use in patients with schizophrenia and schizoaffective disorder: A retrospective survey. J Clin Psychopharmacol. 2000;20:94–98. 10. Machielsen M, Beduin AS, Dekker N, et al. Differences in craving for cannabis between schizophrenia patients using risperidone, olanzapine or clozapine. J Psychopharmacol. 2012;26:189–195. 11. Brunette MF, Dawson R, O’Keefe CD, et al. A randomized trial of clozapine versus other antipsychotics for cannabis use disorder in patients with schizophrenia. J Dual Diagn. 2011;7:50–63. 12. Schwieler L, Linderholm KR, Nilsson‐Todd LK, et al. Clozapine interacts with the glycine site of the NMDA receptor: Electrophysiological studies of dopamine neurons in the rat ventral tegmental area. Life Sci. 2008;83:170–175. 13. Heresco‐Levy U. Glutamatergic neurotransmission modulation and the mechanisms of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:1113–1123. 14. Stahl SM, Shayegan DK. The psychopharmacology of ziprasidone: Receptor‐binding properties and real‐world psychiatric practice. J Clin Psychiatry. 2003;64(Suppl 19):6–12. 15. APA‐American Psychiatric Association. 2000: Diagnostic and Statistical Manual of Mental Disorders‐DSMIV_TR, Text Revision. 4th edn. American Psychiatric Association 2000; Washington, DC. 16. Kay SR, Kalathara M, Meinzer AE. Diagnostic and behavioral characteristics of psychiatric patients who abuse substances. Hosp Community Psychiatry. 1989;40:1062–1064. 17. Montgomery A, Asberg M. A new depression rating scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–389. 18. Lingjaerde O, Ahlfors UG, Bech P, et al. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross‐ sectional study of side effects in neuroleptic‐treated patients. Act Psych Scand Suppl. 1987;334:1–100. 19. Hogan TP, Awad AG, Eastwood RA. Self‐report scale, predictive of drug compliance in schizophrenics—Reliability and discriminant validity. Psychol Med. 1983;13:177–183. 20. Miller WR, Tonigan JS. Assessing trinker’s motivation for change: The stages of readiness and treatment eagerness scale (SOCRATES). Psych Addict Behav. 1996;10:81–89.
Treatment of Patients With Schizophrenia and Cannabis Use
May–June 2014
Ziprasidone Versus Clozapine in the Treatment of Dually Diagnosed (DD) Patients With Schizophrenia and Cannabis Use Disorders: A Randomized Study Thomas Schnell, PhD, Dagmar Koethe, MD, Anna Krasnianski, MD, Stefanie Gairing, MD, Knut Schnell, MD, Jörg Daumann, PhD, Euphrosyne Gouzoulis‐Mayfrank, MD Department of Psychiatry and Psychotherapy, University Hospital of Cologne, Cologne, Germany
Background and Objectives: Clozapine is considered to be particularly effective in the treatment of dually diagnosed (DD) patients with psychosis and substance use disorders. However, its use is restricted by potentially severe side effects. The aim of the present pilot study was to compare the effects of clozapine with the newer second generation antipsychotic (SGA) ziprasidone in DD‐patients. Methods: Thirty (n ¼ 30) patients with schizophrenia and cannabis abuse/dependence were randomized to ziprasidone or clozapine and were followed up for up to 12 months. Results: Cannabis use was reduced in both groups during follow‐up. Clozapine treatment was associated with less positive symptoms of schizophrenia, more side effects and poorer compliance with treatment. Conclusions: Results from this small pilot RCT suggest beneficial effects of both clozapine and ziprasidone in the treatment of cannabis use disorders in psychotic patients. Larger‐scale RCTs are needed in order to assess advantages and disadvantages of the different SGAs in dually diagnosed populations. (Am J Addict 2014;23:308–312)
INTRODUCTION Cannabis use is associated with negative impact on long‐term rehabilitation results in patients with schizophrenia.1 Concerning pharmacologic treatment strategies for patients with
Received April 15, 2013; revised September 29, 2013; accepted October 6, 2013. The present address of Thomas Schnell PhD is Medical School Hamburg (MSH), Am Kaiserkai 1, 20457 Hamburg, Germany. The present address of Dagmar Koethe MD and Knut Schnell MD are Department of Psychiatry and Psychotherapy, University Hospital of Heidelberg, Voßstr. 2, 69115 Heidelberg, Germany. The present address of Euphrosyne Gouzoulis-Mayfrank MD is LVR Clinics Cologne, Wilhelm‐Griesinger Str. 23, 51109 Cologne, Germany. Grant sponsor: Pfizer Pharma. Address correspondence to Dr. Gouzoulis‐Mayfrank, Department of Psychiatry and Psychotherapy, University Hospital of Cologne, Kerpener Str. 62, 50924 Cologne, Germany. E‐mail: [email protected] 308
schizophrenia and comorbid substance use disorders (Dual Diagnosis ¼ DD patients), first generation antipsychotic medications (FGA) may have a negative impact on drug use behavior for two reasons. First, some side effects of FGAs resemble negative symptoms of psychosis, and they may facilitate the urge for self‐medication with drugs or alcohol. Second, as most FDAs are potent selective blockers of dopamine D2 receptors, their direct pharmacologic mechanisms may compromise mesolimbic reward systems, and this may promote addictive behaviors.2,3 Second generation antipsychotics (SGA) are considered helpful in terms of reducing drug use in DD patients, and this may relate to their broader pharmacologic mechanisms affecting dopaminergic and serotonergic systems and their positive impact on negative symptoms.4,5 However, evidence from controlled studies is limited. Clozapine is considered to be particularly effective in the treatment of DD patients, however the evidence mainly derives from uncontrolled studies and case series supporting beneficial effects on psychopathology and craving or drug use.6–10 Only one small randomized study reported diminished use of cannabis in DD patients who were switched from other antipsychotics to clozapine; however, it is not clear whether the previous medication included SGAs or FGAs or both.11 Nevertheless, given the potentially life threatening side effect of agranulocytosis, clozapine is not a first‐line antipsychotic. Many patients will not comply with the required laboratory blood tests or they will not tolerate other common side effects of clozapine such as sedation and weight gain. The main objective of our randomized pilot trial was to study cannabis use behavior in DD patients treated with clozapine compared to another SGA. We chose to study ziprasidone because of its relatively favorable side effect profile which does not include sedation or weight gain, and because of its pharmacological properties. Both clozapine and ziprasidone exhibit a relatively broad receptor profile with only moderate affinities to dopamine and higher affinities to serotonin‐receptors, and this is considered to be advantageous in respect to addiction mechanisms.5 In addition, clozapine
enhances glutamatergic NMDA mechanisms, and this may help to alleviate craving for drugs of abuse.12,13 Finally, ziprasidone inhibits serotonin and noradrenalin reuptake, and this may result in antidepressive effects, which, in turn, may help to reduce relief‐craving in DD patients.14 Hence, both clozapine and ziprasidone may be suitable medications for the treatment of DD patients.
METHODS This pilot study was performed in accordance with the Helsinki Declaration (1964) and was approved by the local ethics committee of the University of Cologne, Germany. After full verbal and written information about the study, patients gave written informed consent for their participation with the explicit notion that they were free to withdraw their consent at any time without having to disclose the reasons and without any consequences for their further treatment. The study was registered in EudraCT (European Union Drug Regulating Authorities Clinical Trials, EudraCT‐Number: 2005‐003156‐35). Participants We planned to randomize 50 dually diagnosed in‐patients with schizophrenia, schizophreniform or schizoaffective disorder according to DSM‐IV as well as cannabis abuse or dependence according to DSM‐IV to either ziprasidone or clozapine treatment. Exclusion criteria were further Axis I psychiatric disorders or relevant neurologic disorders affecting brain function and acute positive symptoms interfering with the capability to give informed consent. Study Procedures At baseline (t0), we reviewed the medical records of all patients and performed a detailed interview on demographics, a Structured Clinical Interview (SCID I for DSM‐IV)15 and an additional detailed interview on patterns of cannabis use including age at onset of use, time since last use, average frequency of use (joints per month) and maximum frequency of use (joints per month), duration of regular cannabis use (months), as well as the age at onset of the psychotic disorder. Psychiatric symptoms and level of functioning were assessed by one single rater (T.S.) by means of the PANSS,16 Montgomery Asberg Depression Scale17 and the Global Assessment of Functioning Scale (GAF) according to DSM‐ IV.15 The UKU Side Effect Rating Scale18 was used to assess side effects of medication and the Drug Attitude Inventory19 to evaluate compliance with the medication (indicator of medication adherence). The motivation to stop or reduce cannabis use was assessed by means of the standardized questionnaire SOCRATES.20 After completion of the baseline assessments, patients were randomized to treatment with ziprasidone or clozapine. Treatment allocation was concealed in 50 opaque, security‐ sealed envelopes, which were held in a packet in a locked Schnell et al.
cabinet. Envelopes contained a sheet of paper typed with clozapine or ziprasidone (25 envelopes each). Randomization was conducted by a person independent to the study by means of randomly drawing and opening an envelope from the packet. The result of randomization was given to the study administrator, who informed the attending psychiatrist of the patient’s treatment allocation. After randomization, drug dosage and concomitant medications were flexible and adjustable depending on clinical requirements. There were no limitations in doses, concomitant medications and combinations. Decisions for drop‐out from study medications were taken by the attending psychiatrist together with the patient on the basis of clinical evaluations of effectiveness and/ or side effects. After discharge from hospital, all patients were offered integrated treatment for both the psychotic and drug use disorder in the out‐patient unit of the Department. The treatment included pharmacotherapy, clinical management with supportive and motivational elements, psychoeducation, cognitive behavioral group therapy and support for social and occupational rehabilitation. Patients underwent follow‐up assessments by the same rater (T.S.) at fixed time points 3, 6, and 12 months after inclusion in the study (t1, t2, t3), irrespective of the actual medication and setting in which they were treated (out‐patient unit of the Department or again in‐ patient setting after readmission). At follow‐up assessments, we reviewed the medical records and performed detailed interviews with the patients, a family member or significant other and the attending psychiatrist. We verified compliance with the antipsychotic drug regimen by means of assessments of drug plasma levels (Institute of Neurochemistry, University Hospital of Mainz, Department of Psychiatry and Psychotherapy). We assessed cannabis use during the months since the last visit (primary outcome variable: average frequency of use in joints per month). Finally, we complemented the interview results by toxicological screens in urine samples (enzyme‐ multiplied immunoassay, von Minden GmbH) and toxicological hair analysis (Institute of Legal Medicine of the University of Cologne). In addition, we evaluated the overall clinical course, assessed exacerbations of the psychotic disorder and rehospitalizations, compliance with the treatment (operationalized as percentage of completed vs. scheduled therapy sessions) and unscheduled presentations on an emergency basis. Finally, we assessed psychopathology, side effects and compliance with medication and motivation to reduce drug use by means of the same standardized instruments as in the baseline examination. Statistical analyses We performed both Intention to Treat (ITT) and Treated per Protocol analyses (TPP). Regarding the ITT condition, we applied the last observation carried forward (LOCF) method as a very conservative means of analysis with the data of all patients who reached the first follow‐up examination (t1). Demographic variables and baseline clinical characteristics were compared between groups by means of chi‐square and May–June 2014
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unpaired t tests. Regarding the analyses of follow‐up data, we compared the two groups by means of multivariate analyses of variance (MANCOVA) with repeated measurements including two covariates1 length of time of initiating inpatient treatment and2 follow‐up treatment setting (inpatient, day hospital, and outpatient). Levels of significance were corrected according to Bonferroni. All procedures were performed using SPSS version 15 (SPSS, Inc., Chicago, IL).
RESULTS Thirty patients were included in the study, 16 patients were randomized to receive ziprasidone treatment and 14 received clozapine. The study had to be closed after the 30 patients because of circumstances unrelated to the study (move of the principal investigator to another institution). The sample was predominantly male (86.7%) with a mean age of 29 years (SD 8.1). On average, the first psychotic episode had been 43.9 months prior to inclusion in the study (SD 36.4), patients had
experienced on average 5 previous psychotic episodes (SD 9.2). Regarding cannabis use disorders, 27 patients were diagnosed with dependence, and 3 patients with cannabis abuse. There were no significant differences between the two groups with respect to demographic and baseline clinical characteristics (Table 1). The average daily dose of clozapine was 225 mg (range: 50–425 mg), and the average dose of ziprasidone was 200 mg (range: 80–400 mg). Antipsychotic drug plasma levels were compatible with the prescribed doses. Twelve out of the 30 patients finished the study regularly after the treatment period of one year (7 patients in the ziprasidone group, 5 patients in the clozapine group). Eleven patients dropped out before t1, 5 patients before t2 and 2 patients before t3. Reasons for drop outs in the clozapine group were: sedation (n ¼ 7), extreme hypersalivation (n ¼ 1) and fever (n ¼ 1). Reasons for drop outs in the ziprasidone group were: agitation (n ¼ 2) and insufficient antipsychotic efficacy (n ¼ 7). There were significant differences concerning co‐medications between groups (chi‐square ¼ 11.72; p ¼ .039). Patients
TABLE 1. Comparison of demographic and baseline‐data (t0) between groups
Descriptive statistics
Gender (male/female) Mean age in years (mean, SD) Level of graduation Employment† Partnership (single/with partner) Housing‡ Time since diagnosed with schizophrenia (months, mean and SD) Mean age in years at onset of cannabis use (mean, SD) Number of psychotic episodes (mean, SD) Time between onset of cannabis use and diagnosed with schizophrenia (months, mean, and SD) Time since last cannabis use (days, mean, and SD) Average frequency of cannabis use (joints per month) Maximum frequency of cannabis use (joints per month) Duration of regular cannabis use (months, mean and SD) PANSS positive symptoms (mean, SD) PANSS negative symptoms (mean, SD) PANSS general psychopathology (mean, SD) MADRS (mean, SD) GAF score (mean, SD) DAI (mean, SD) SOCRATES taking steps (mean, SD) SOCRATES recognition (mean, SD) SOCRATES ambivalence (mean, SD)
Statistics
Ziprasidone (n ¼ 16)
Clozapine (n ¼ 14)
df
Value
p
14/2 27.5 (5.0) 1/5/4/4/2 13/0/2/0/1 16/0 10/5/0/0/1 39.69 (33.79) 16.13 (2.39) 3.4 (3.5) 82.38 (40.76)
12/2 30.71 (10.5) 2/4/7/0/1 12/1/0/1/0 14/0 9/2/1/1/1 48.71 (40.08) 17.43 (4.52) 6.9 (12.8) 80.79 (70.53)
1 28 4 4 1 4 28 28 28 28
021§ 1.089¶ 1.211|| 4.929§ x 3.219§ .669¶ 1.006¶ 1.108¶ .077¶
.886 .286 .236 .295 x .522 .509 .323 .277 .939
46.88 (61.68) 115.5 (147.94) 340.38 (303.37) 97.50 (40.55) 13.75 (2.69) 13.50 (6.45) 33.63 (7.1) 13.56 (4.86) 47.25 (11.78) .25 (4.84) 6.93 (4.29) 2.18 (3.14) 1.56 (2.03)
23.57 (23.52) 114.14 (228.48) 302.14 (216.48) 114.64 (91.65) 15.57 (5.47) 17.93 (10.2) 38.21 (6.46) 14.79 (6.67) 43.36 (8.75) .43 (3.85) 7.35 (5.42) 1.5 (2.21) .85 (1.35)
28 28 28 28 28 28 28 28 28 28 28 28 28
1.329¶ .020¶ .392¶ .678¶ 1.180¶ 1.440¶ 1.842¶ .579¶ 1.015¶ .111¶ .236¶ .683¶ 1.102¶
.195 .985 .698 .504 .248 .161 .076 .567 .319 .913 .815 .500 .280
None/elementary school degree after form 9/intermediate school degree after form 10/A‐level after form 13/university degree;; †Jobless/full job/part time job/ pension/other;; ‡Alone/with family/assisted living/homeless/other;; §Chi‐square;; ¶T‐Value;; ||Z‐Value (Mann–Whitney U‐test); df, degrees of freedom; SD, standard deviation; p, level of significance; PANSS, positive and negative syndrome scale; MADRS, Montgomery‐Asberg Depression Rating Scale; GAF, global assessment of functioning scale; DAI, drug attitude inventory; SOCRATES, stages of change readiness and treatment eagerness scale.
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treated with ziprasidone were more likely to get additional antipsychotics, whereas patients treated with clozapine were more likely to get antidepressant co‐medications. There was no significant difference in time‐to‐dropout between the two groups (chi‐square ¼ 2.5; p ¼ .475). Regarding the primary outcome variable (average frequency of cannabis use) LOCF analysis as well as the TPP analysis with the patients who reached the last observation point after 12 months, yielded comparable findings. The data are presented in Figure 1. No patient had to be excluded from analyses due of incompatibilities between the different sources of data information (medical records, interviews with patients, significant others and the attending psychiatrist, toxicological screens in urine, and hair samples). The two covariates (length of time of initiating inpatient treatment and follow‐up treatment setting (inpatient, day hospital and outpatient)) were below significance at all follow‐up examinations (p > .08). Hereafter, we present the data of the TPP analysis. The complete statistical analyses can be obtained upon request from the first author. Both groups reduced the frequency of cannabis consumption during follow‐up (main effect of time: F ¼ 7.15; p ¼ .023). The reduction of cannabis use was already seen at the first follow‐up examination (t1) and was stable over the period of 12 months with no differences between the two
A
ITT analysis (LOCF)
400 350 300 250 200
Ziprasidone (n=11)
150
Clozapine (n=8)
100 50 0 t0
t1
B
t2
t3
TPP analysis
450 400 350 300 250
Ziprasidone (n=7)
200
Clozapine (n=5)
150 100 50 0 t0
t1
t2
t3
FIGURE 1. Frequency of cannabis use (joints per month, means and SD) during baseline (t0) and follow‐up examinations (t1: 3 months, t2: 6 months, t3: 12 months after baseline), according to both ITT (1a) and TPP analysis (1b). ITT, intention to treat; LOCF, last observation carried forward; TPP, treatment per protocol.
Schnell et al.
groups (main effect of group: F ¼ 2.75; p ¼ .128) and no interaction time treatment (F ¼ 2.14; p ¼ .174). The PANSS positive scale score decreased over time for both groups (main effect of time: F ¼ 5.37; p ¼ .004). The group effect was below significance (F ¼ 2.811; p ¼ .056). However, the interaction effect (time treatment) was significant and pointed to a stronger decline of positive symptoms in the clozapine group (F ¼ 3.11; p ¼ .05). In line with that, there was a significant between‐group effect concerning treatments on an emergency basis with more consultations in the ziprasidone group (F ¼ 7.29; p ¼ .022). Further significant time treatment interactions were identified regarding compliance with treatment. Patients treated with ziprasidone evaluated their medication more positively (score of the drug attitude inventory) and they attended more regularly their group psychotherapy sessions (F ¼ 5.21; p ¼ .005, and F ¼ 4.51; p ¼ .024, respectively). Finally, there was a significant between‐group effect on side effects unfavoring the clozapine group (F ¼ 8.2; p ¼ .017). A detailed analysis of the UKU Rating Scale data on a single item level revealed that this was primarily due to hypersalivation.
DISCUSSION The present pilot study aimed to compare the effects of clozapine and ziprasidone on cannabis use in dually diagnosed (DD) patients with psychosis and cannabis use disorder. Thirty DD patients were randomized to ziprasidone or clozapine and were followed up for up to 12 months. Both antipsychotics were followed by improvement of psychotic symptoms and reductions of cannabis use. Clozapine treatment was associated with a stronger reduction of positive symptoms, but more side effects. Patients treated with ziprasidone evaluated the medication more positively and they showed an overall higher adherence with the psychosocial treatment compared to the clozapine group (more frequent attendance of group psychotherapy sessions). Our findings suggest that besides clozapine, ziprasidone (and probably also other SGAs) may also be suitable medications for the treatment of dually diagnosed patients. Hence, the clinical decision for an antipsychotic medication should be based on the clinical symptom profile of the individual patient such as withdrawal and apathy or agitation, and on the side effect profile of the antipsychotic drug favoring activation or sedation. Interestingly, some of the patients in the present trial felt that the sedating effects of clozapine helped to diminish craving for cannabis, while other patients suffered from sedation. Some patients treated with ziprasidone appreciated the activating effects of this medication, whereas two patients reported that some (over)excitement after ziprasidone was associated with stronger craving. Several important limitations of this study have to be acknowledged: First, the sample size was small and drop‐out rates were high, and this can easily skew the results. Furthermore, very few patients treated with clozapine finished May–June 2014
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the study, and clozapine is known to require several months to reach its full efficacy. Second, both patients and raters were not blind to the treatment condition. Third, the attending doctors were allowed to adjust the dose of the study medications and give co‐medications according to clinical requirements, and this renders conclusions on the effects of the study medications difficult. Finally, less specific aspects of treatment and care, such as the participation in the clinical trial, the increased attention and general support and the psychotherapeutic program may have contributed to the reduction of substance use in both groups. In conclusion, the present pilot study has important methodological limitations. Nevertheless, it does suggest that both clozapine and newer SGAs may be suitable medications for the treatment of DD patients. Larger‐scale RCTs are needed in order to assess advantages and disadvantages of different SGAs in this population. In the meanwhile, clinicians should come to individual decisions based on the symptom profile and preferences of the individual patients as well as the effects and side effect profile of the different SGAs. The present study was supported by a grant from Pfizer Pharma (Karlsruhe, Germany) to the last author (investigator initiated trial). Apart from financial support, Pfizer had no influence on any aspect of the study such as design, data collection, statistical analyses, interpretation of data and drafting the manuscript. The authors thank Prof. Dr. C. Hiemke (Institute of Neurochemistry, University Hospital of Mainz) for the assessments of drug plasma levels, and Prof. Dr. H. Käferstein (Institute of Legal Medicine, University Hospital of Cologne) for the toxicological hair analyses. Declaration of Interest This investigator initiated trial (IIT) was supported by Pfizer Pharma. Authors report no other conflicts of interest.
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